Vasoconstricting and bronchodilating compositions and methods utilizing gallic acid and alkyl gallates

ABSTRACT

PHARMACEUTICAL COMPOSITIONS CONTAINING ALKYL GALLATES OR GALLIC ACID AND ADAPTED FOR ADMINISTRATION TO THE RESPIRATORY SYSTEM CAN BE EMPLOYED FOR TREATING NASAL DECONGESTION AND BRONCHOSPASMS.

United States Patent 3,639,622 VASOCQNSTRICTING AND BRONCHODILATING COMPOSITIONS AND METHODS UTILIZING GALLIC ACID AND ALKYL GALLATES Paul Gre engard, Hamden, Conn., and Barbara Petrack, Brrarclrlf Manor, N.Y., assignors to Geigy Chemical Corporation, Ardsley, N .Y.

No Drawing. Continuation-impart of abandoned applicatron Ser. No. 509,611, Nov. 24, 1965. This application Nov. 22, 1968, Ser. No. 778,320

Int. Cl. A61k 27/00 US. Cl. 424-308 16 Claims ABSTRACT OF THE DISCLOSURE Pharmaceutical compositions containing alkyl gallates or gallic acid and adapted for administration to the respiratory system can be employed for treating nasal decongestion and bronchospasms.

CROSS-REFERENCE This is a continuation-in-part of copending application Ser. No. 509,611, filed Nov. 24, 1965, now abandoned. doned.

DETAILED DESCRIPTION The present invention pertains to decongestant and bronchodilating compositions adapted for administration through the respiratory system and containing a compound of the formula:

I HO

wherein R is hydrogen or alkyl of from 1 to 9' carbon atoms. Such alkyl groups can be straight or branch chained and include such groups as methyl, ethyl, propyl, isopropyl, butyl, pentyl, octyl, nonyl and the like.

It is known that naturally occurring sympathetic catecholamines such as epinephrine and norepinephrine have potent vasoconstricting and bronchodilating properties which make them useful as decongestants. It is also known that a large number of amines, the so-called sympathomimetic amines which resemble norepinephrine and epinephrine chemically and pharmacologically, share these properties. The mechanism of the latter group is not fully understood. It appears however that While they may possess some direct action, they depend largely upon the presence of the naturally occuring catecholamines, their principal action involving the release of endogenous catecholamines.

The presentinvention is based on the discovery that gallic acid and alkyl gallates effectively prevent the catabolism of norepinephrine and epinephrine and thereby enhance the above pharmacological properties of these compounds. It is accordingly possible to enhance the nasal and bronchial decongestant properties of endogenous catecholamines through the use of pharmaceutical compositions which are adapted for intrarespiratory use and which contain either gallic acid or an alkyl gallate. Moreover, since the mode of action of exogenous sympathetic and sympathomimetic amines involves release of the endogenous catecholamines, the nasal and bronchial decongestant properties of the former group are also enhanced through the concommitant administration of gallic acid or an alkyl gallate.

The administration of gallic acid or an alkyl gallate in the practice of the present invention for nasal decongestion, alone or in combination with a sympathetic or 3,639,622 Patented Feb. 1, 1972 sympathomimetic amine decongestant, is efiFected through the use of a pharmaceutical composition adapted for intranasal administration. These compositions include nasal sprays, solutions and water soluble jellies.

The administration of gallic acid or an alkyl gallate for bronchodilation, alone or preferably in combination with a sympathetic or sympathomimetic bronchodilator is effected through the use of a pharmaceutical composition adapted for inhalational administration, such as solutions which may be dispensed through the aid of an aerosol inhalation vaporizer.

While the gallic acids of the present invention can also be given orally alone or in combination with a sympathetic or sympathomimetic amine, in compositions such as tablets or capsules, compositions adapted for intranasal or inhalational administration are preferred.

Generally the gallic acid or alkyl gallate will be present in such compositions in an amount of from 0.5 to about 5.0%, preferably from about 1 to about 2%. When a sympathetic or sympathomimetic amine is employed in the composition, its concentration will naturally be dependent upon its relative potency. Generally the gallic acid or alkyl gallate is present in an amount fromtwo to forty times that of the amine component. Thus while the compositions will contain from 0.01 to 0.05% to epinephrine, norephinephrine, or isoproterenol and from 1 to 2% of the gallic acid or alkyl gallate, those utilizing ephedrine, phenylephrine or metaproterenol will contain from about 0.1 to about 0.5% of the sympathomimetic amine and 1 to 2% of the gallic acid or alkyl gallate. Preparation and use of different dosage concentrations permits greater flexibility for treatment since factors such as the age of the individual and the severity of particular conditions can be taken into consideration. The actual dosage administered is adjusted to need and depends upon the response elicited, with observance of the usual precautions dictated by sound professional practice.

In view of the nature of the administration, solutions and water soluble jellies represent the preferred pharmaceutical forms for intranasal administration. Thus, simple sterile aqueous solutions or isotonic saline solutions can be administered through the use of irrigation, drops, sprays or tampon. Other agents such as antihistamines, stabilizers, wetting agents, antibacterial agents and the like can also be present.

For inhalational administration, the preferred pharmaceutical form is a solution or fine particle suspension for dispensation via an aerosol vaporizer or nebulizer.

While the overall decongestant and brochodilating properties in gallic acid and alkyl gallates can be readily observed in actual use, a quantitative measurement of the ability of these compounds to enhance the activity of sympathetic catecholamine and sympathomimetic amine decongestants requires somewhat more involved procedures. In one such procedure dogs of either sex are anesthetized with pentobarbital (30 mg./kg.) and placed in a supine position. The right femoral vein is exposed for additional injections of pentobarbital as necessary. A midline incision below the thyroid catilage is made in order to expose and cannulate the trachea. The cannula is connected to a Harvard pump and artificial respiration is then maintained throughout the remainder of the experiment. Approximately 1 inch cephalic to the trachea cannula, the trachea is again out, permitting insertion of a balloon and tube leading from the balloon. The balloon is pushed upward into the pharynx and inflated sufficiently to occlude the pharynx. Blood pressure is recorded from the left femoral artery.

Nebulizer equipment is connected to an air source via a constant pressure regulating valve set to deliver air at mm. Hg In addition, a mercury column blowoff valve is inserted into the system to serve as an additional check against any changes in the pressure at its source. The pressure is recorded on a polygraph. The pressure line is then divided so that air can be sent through either nebulizer A or nebulizer B. Both nebulizers are connected back into one line which is then connected to the nasal catheter. A side tube is connected to a second transducer and this nasal back pressure is also recorded on the polygraph. If resistance in the nares increases, nasal back pressure increases and vice versa.

The nasal catheter is inserted into the right nares and the finger cot inflated. Nebulization is started using atomizer A which contains 9 ml. of a 20% reagent grade glycerine in saline (8.5 g./liter). Nebulization is continued until back pressure is elevated indicating that congestion has been produced. The test drugs are administered directly into the nasal passage in droplet form in a volume of 0.5 ml.

The results of such an experiment utilizing butyl gallate and epinephrine are as follows:

0.01% Epinephrine with 2% butyl gallate As can be seen from the above, a solution of 0.01% of epinephrine reduces back pressure by an average of 2.9 mm. Hg. A 1% solution of phenylephrine produces a like response, 3 mm. Hg. However when 2% butyl gallate is combined with 0.01% epinephrine, the average reduction in back pressure is 4.0 mm. Hg. More significantly, the average time required to achieve this response is reduced by 45%. It is also significant that no increase in arterial blood pressure was observed.

The following examples further illustrate the preparations of the present invention and processes for obtaining them.

EXAMPLE 1 A 1% topical nasal solution of propyl gallate is prepared by dissolving an appropriate quantity in sterile water, maintaining aseptic technique throughout. The solution is sterilized by bacteriologic filtration and filled into sterile glass dropper bottles. This solution is administered topically by dropping appropriate quantities into the nostrils in accordance with the need.

EXAMPLE 2 A nasal jelly is prepared by mixing propyl gallate with a water soluble jelly base. The propyl gallate is present in the amount of 1% based on the jelly base. An appropriate dosage is a pea-sized globule inserted in the nostril.

EXAMPLE 3 A topical nasal spray preparation containing 2% by weight of butyl gallate and 0.1% of ephedrine in sterile water is prepared and introduced into a plastic squeeze bottle. This is administered by discharging the spray directly into the nostrils.

EXAMPLE 4 The following gallates, all of which are known or can be synthesized readily by techniques familiar to those skilled in the art, are converted to dosage forms analogous to those of Example 1, 2 or 3:

isopropyl gallate octyl gallate nonyl gallate gallic acid methyl gallate ethyl gallate In the case of aqueous solutions of octyl gallate or nonyl gallate, a solubilizing agent such as polyoxyethylene ricinoleate is used.

EXAMPLE 5 A sterile aqueous solution of 0.5% phenylephrine, 1.5% butyl gallate, 0.5% thenyldiarnine hydrochloride and 0.025% benzalkonium chloride is utilized as a nasal spray for the relief of nasal congestion in the common cold, allergic rhinitis, vasomotor rhinitis and sinusitis.

EXAMPLE 6 Ingredient: Amount Butyl gallate gm 1.000 Sorbitan monooleate polyoxyethylene gm 12.5 00 Phenylmercuric acetate gm 0.002 Distilled water q.s. ad. ml 100.000

The butyl gallate and phenylmercuric acetate are dissolved in a solution of the sorbitan monooleate polyethylene in a portion of the water and sufiicient additional water is added to bring the volume to ml. The 1% solution is suitable for drops or nasal spray.

The butyl gallate, epinephrine hydrochloride, sodium bisulfite and phenylmercuric acetate are dissolved in a s0- lution of sorbitan monoleate polyethylene and the solution is adjusted to a final volume of 100 ml. The above should be filled under nitrogen or carbon dioxide.

The following prescriptions are prepared in the same fashion:

Butyl gallate gm 2.000 Norepinephrine hydrochloride gm 0.050 Sorbitan monooleate polyoxyethylene gm 25.000 Sodium bisulfite gm 0.100 Phenylmercuric acetate gm 0.002 Distilled water q.s. ad ml 100.000

Butyl gallate gm 2.000 Ephedrine sulfate gm 0.500 Sorbitan monooleate polyoxyethylene gm 25.000 Sodium bisulfite gm 0.100 Phenylmercuric acetate gm 0.002 Distilled water q.s. ad ml 100.000

Propyl gallate gm 1.000 Isoproterenol hydrochloride gm 0.010 Sorbitan monooleate polyoxyethylene gm 12.500 Sodium bisulfite gm 0.100 Phenylmercuric acetate gm 0.002 Distilled Water q.s. ad ml 100.000

EXAMPLE 8 Ingredient: Amount Butyl gallate gm 1.000 Sorbitan monooleate polyoxyethylene gm 12.500 Tragacanth gm 1.000 Glycerin gm 15.000 Phenylmercuric acetate gm 0.002 Distilled water q.s. ad ml 70.500

The tragacanth is dissolved in /2 the water while the remaining four ingredients are dissolved in the remaining water. The two are thoroughly mixed to yield a 1% nasal i y- If a sympathetic catecholamine or sympathomimetic amine decongestant is included, it is dissolved With the butyl gallate prior to mixing with the tragacanth gel.

EXAMPLE 9 Fifteen milliliters of fine particle suspension of 30.0 mgfof isoproterenol sulfate and 225mg. of butyl gallate in an inertnontoxic aerosol propellant are introduced into a standard pharmaceutical metal aerosol container having a single dose value designed to release single dosage volume of .0375 ml. each. The aerosol can be equipped with an oral adapter.

What is claimed is:

1. The method of potentiating the nasal and bronchial decongestant properties of sympathetic catecholamines or sympathomimetic amines which comprises the intranasai or oral inhalational administration to an individual of an effective amount of a pharmaceutical composition cont'ainingffrom about 0.5 to about 5.0% of a compound of the formula:

no-Go o n wherein R is hydrogen or alkyl of from 1 to 9 carbon atoms.

2. The method of claim 1 wherein said sympathetic catecholamine or sympathomimetic amine is epinephrine, norepinephrine, ephedrine, isoproterenol or phenylephrine.

3. The method of claim 2 wherein said pharmaceutical composition is adapted for intranasal administration and is a solution or water soluble jelly containing from about 1 to about 2% of propyl gallate or butyl gallate.

4. The method of claim 3 wherein said sympathetic catecholamine is endogenous epinephrine or norepinephrme.

5. The method of claim 3 wherein said sympathetic catecholamine or sympathomimetic amine is exogenous and is administered in combination with propyl gallate.

6. The method of claim 3 wherein said sympathetic catecholamine or sympathomimetic amine is exogenous and is administered in combination with butyl gallate.

7. The method of claim 2 wherein said pharmaceutical composition is adapted for oral inhalation and is a solution or fine particle suspension containing from about 1 to about 2% of propyl gallate or butyl gallate.

8. The method of claim 2 wherein said sympathetic catecholamine or sympathomimetic amine is exogenous and is administered in combination with from about 1 to about 2% of propyl gallate in a pharmaceutical composition adapted for oral inhalation, said composition being a solution or fine particle suspension.

9. The method of claim 2 wherein said sympathetic catecholamine or sympathomimetic amine is exogenous and is administered in combination with from about 1 to about 2% of butyl gallate in a pharmaceutical composition adapted for oral inhalation, said composition being a solution or fine particle suspension. i

10, A pharmaceutical composition according to claim 8 wherein said. composition is adapted for intranasal administration and is an aqueous solution, an intranasal spray or a water soluble jelly, comprising from about 1 to about 2% of propyl gallate or butyl gallate.

11. A pharmaceutical composition according to claim 10 containing propyl gallate and a decongestant amount of epinephrine, norepinephrine, ephedrine, isoproterenol or phenylephrine. I

12. A pharmaceutical composition according to claim 10 containing butyl gallate and a decongestant amount of epinephrine, norepinephrine, ephedrine, isoproternol or phenylephrine.

13. A pharmaceutical composition according to claim 18 wherein said composition is adapted for oral inhalation comprising from about 1 to about 2% of propyl gallate or butyl gallate.

14. A pharmaceutical composition according to claim 13 containing propyl gallate and a bronchodilating amount of epinephrine, norepinephrine, ephedrine, isoproterenol or phenylephrine.

15. A pharmaceutical composition according to claim 13 containing butyl gallate and a bronchodilating amount of epinephrine, norepinephrine, ephedrine, isoproterenol or phenylephrine.

16. A pharmaceutical composition adapted for intranasal or oral inhalational administration comprising from about 0.5 to about 5.0% of a compound of the formula:

HO- COOR wherein R is hydrogen or alkyl of up to 9 carbon atoms, a decongestant amount of a sympathetic catecholamine or a sympathomimetic amine decongestant and a pharmaceutical carrier suitable for nasal or oral inhalational administration.

UNITED STATES PATENTS References Cited 3,279,988 10/1966 Buting et a1. 424272 OTHER REFERENCES Chemical Abstracts, vol. 44, 1950, p. 4201D.

ALBERT T. MEYERS, Primary Examiner D. M. STEPHENS, Assistant Examiner US. Cl. X.R. 

